Evaluating AT1R expression and the effects of renin-angiotensin system inhibition in a mouse model of cerebral amyloid angiopathy.

INTRODUCTION

The renin-angiotensin-aldosterone system (RAAS) has been shown to be dysregulated in dementia, with elevated levels of angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptors (AT1Rs). Cerebral amyloid angiopathy (CAA), a dementia-causing cerebrovascular disease, currently has no treatment or cure available. We assessed whether a mouse model with CAA (Tg-SwDI) exhibits elevated levels of AT1Rs and whether RAAS-targeting drugs (telmisartan and lisinopril) affect these levels.

MATERIALS AND

METHODS

Tg-SwDI mice were treated with sub-depressor doses of either telmisartan or lisinopril from 3 to 8 months of age, with blood pressure being monitored 2 and 4 months after the start of treatment. Post-mortem, receptor autoradiography was performed to determine levels of AT1R in 13 brain regions in untreated and treated Tg-SwDI mice compared to untreated wild-type controls (C57BL/6J mice).

RESULTS

No statistically significant differences among groups were observed in AT1R levels in any of the 13 brain regions analyzed. Although sexual dimorphism in blood pressure was observed in both wild-type and Tg-SwDI mice (males > females), drug treatment did not significantly lower blood pressure in Tg-SwDI mice, confirming the delivery of sub-depressor doses.

CONCLUSIONS

Regional brain AT1R levels were not significantly dysregulated in Tg-SwDI mice compared to wild-type mice. Additionally, drug treatment with sub-depressor doses of the AT1R antagonist, telmisartan, or the ACE inhibitor, lisinopril, caused no significant brain AT1R alterations in Tg-SwDI mice. This suggests that pathophysiological changes in the brain renin-angiotensin system do not mediate the cognitive impairments and neuropathological changes associated with CAA in Tg-SwDI mice.